Process for the production of substituted 5-aminopyrazoles



thereof.

Unite PROCESS FOR THE PRODUCTION OF SUBSTI- TUTED S-AMINOPYRAZOLES Heinrich Gold, Koln-Stammheim, and Peter Kurtz, Leverkusen-Bayerwerk, Germany, assignors to Farbenfabriken Bayer Aktiengesellschaft, Leverkusen, Germany, a corporation of Germany No Drawing. Filed Jan. 28, 1959, Ser. No. 789,508 Claims priority, application Germany Feb. 4, 1958 Claims. (Cl- 260-310) This invention relates to a process for the production of S-aminbpyrazoles and is more particularly concerned with the production of substituted S-aminopyrazoles by reacting a substituted or unsubstituted l-cyano-propadi- 1,2-ene upon hydrazine or a monosubstitution product States Presto products thereof, such aster example l-cyrano-he'x'atri- 1,2,5-ene, l-cyano-heptatri-1,2,5 ene or Z-cyano-butadi- 2,3-ene, are also suitable for use in the process-of the invention. These compounds can be prepared by methods .known per se or by reacting l-halogeno-prop-Z-yhes, which may be substituted, in aqueous acid solution in the presence of catalytic quantities of a cuprous compound with hydrogen cyanide (in this connection see for example Examples 1 and 8). Instead of the pure l-cyanopropadi-LZ-enes, it is also generally possible to use mixtures of these 1-cyano-propadi-l,2-enes with the. corre- 7' sponding isomeric alkynenes, such as'areformedwhen using theprocedure referred to above,

When l-cyano-hexatri-1,2,5-ene is tion product contains l-cyanohex-5 ene-2-yne as an imprepared, the reacpurity and, when lcyano-heptatri-1,2,5-ene is prepared,

the reaction'product still contains l-cyano-hepta-S-ene-Z- yne as an impurity. lfl-cyano-propadi-1,2-ene is prepared by this method, the reaction product still contains small quantities of 1-cyano 2-chloroprop-2 ene. This reaction product can also ing to the invention, since 1-cyano-2-ehlor0prop-2-ene yields the same reaction product as 1-cyano-propadi-1,2- ene. Y

. 7 Suitable monosusbtituted hydrazines are the hydrazines of the aliphatic, aromatic and heterocyclic series, such as for example fi-hydroxyethyl hydrazine, fi-cyanoethyl hydrazine, phenyl hydrazine, p-carboxyphenyl hydrazine, 3-sulfophenyl hydrazine, 8-sulfonaphthyl( 1 -hydrazin e, p-nitrophenyl hydrazine, benzthiazolyl-( l -hydrazine, and also 4,4'-dihydrazinostilbene-2,2 disulfonic acid. The, reactants for the process of theinventionare in generaluse d in about'equivalent quantities, i.e. one-mol of a l-cyanO-propadi-LZ-ene is employed per mol of a mono-hydrazine or 0.5 mol of a dihydrazine. A more be used for the reaction accordi specific embodiment resides in the preparationofan N-substituted '5-am1nopyrazole by reacting,0.5 mol of the unsubstituted hydraz neflwith 1 mol of a l-cyano-propadil ene. The reaction itself is preferably carried ,out'in a solvent, such as for example methanol or water lt is The reaction generally proceeds exothermically,

a vantageous towork in a weakly. alkaline; or neutral s I s I solutions are added are so controlledthat th so that it may be advisable to cool the reactionmixture so that the temperatures reached are not too high. It is however advantageous to work at somewhat elevated temperatures, for example at temperatures in the range from 20 to 50 C. In order to complete the reaction, it may be desirable to follow the latter by heating for some time at relatively high temperatures, for example up to 100 C. This step is particularly to be recommended when the ring closure to form the aminopyrazoles takes place with some ditliculty. In these cases, it is also possible to add min- J 'eral acid.

The S-aminopyrazoles obtained according to the proo essof the invention can be used in known manner for the manufacture of dyes (see for example British patent specification No. 802,097). V s

Example 1 33 parts by weight of 1-cyanopropadi-.1,2-ene are introduced dropwise and while stirring into a mixture of 54 parts by weight of phenyl hydrazine and 200 parts by volume of methanol, introduction being effected at such a rate that the temperature does not exceed 30 C. The I mixture can also be suitably cooled with iced water. After the dropwise addition has beencompleted, the tempera,"

ture is kept for another 2 hours at 30 C. A mixture of 300 parts by volume of water and 50 parts by volume of concentrated hydrochloric acid is then added and'thereactionsolution distilled until the temperature of the boilingmixture is 95 C. 69 partsby weight of1-phenyl-3- .methyl-Sgaminopyrazole precipitate from the distillation; residue cooled to 20 of the theoretical.

The same product can way:

dropwise over a period of 35 minutes to a solution parts by weight ofphenyl hydrazine in 50 parts by volume of benzene. Due to the heat of reaction, the temperature .risesto 85 C. The mixture is then kept for 1 hour at 8 0 C. and thereafter cooled. 25.9 parts by weightof" cyanacetone-phenyl hydrazone are crystallized out; me1t-' ing point after recrystallization: 98-99" C. By concen-'- trating the'mother liquor by evaporation, another 2 9.0= parts by weight of the .reactionproduct are obtained. 1 a

12.2 parts by weight of the cyanacetone-phenyl hydra-, r

zone described above are heated for 30 minutes to 809 C.

substance is 1-phenyl-3.-methyl-5 aminopyarzole. f

pared in the following'manner: V 1

2500 parts by volume .ofsaturated'sodiurnbhloride solution are placed in a round-bottomed flask with "a fitted reflux condenser and two dropping fuunels 50 parts by weight of cuprous chloride, about 2 parts by weight'of copper powder and 50 parts by volume of; concentrated hydrochloric 'acid are added thereto. T hei mixture is then heated to 70-75 C." Two electrodes dip into theflask, these electrodes being connected to a recording pH-measuring instrument. Such a quantityof la 30% sodiumcyanfide solution isnow supplied by. way" f of the droppingfunnels that the p'H value isadjuste at the same time additional quantities of-sodiirm solution are introduced. The .SPeeds-atwhic Patented Mar.-14,' 1961 v C., on the addition of 60 parts by volume of 40% sodium hydroxide solution. The melting: point of the crudeproduct is IDS-111 C. and, after re .crystallization from benzene, is 1l6 Yield;

also beobtained in the following 20 parts by weight of l-cyanopropadi-LZ-n are aada, if

.The 1-cyanopropadi-1,2-ene which is employed ispre- 1 3-4. Thereafter, over a period of 4 hours, .150 by weight of 1-chloro-prop-2-yne are addeddro wise and pH "value does not change throughout the entire experipH value remains constant when the supply of sodium cyanide is shut off. The reaction product can be separated from the catalyst solution by decanting or by steam distillation, and ,is thereafter dried. The crude product "still contains small quantities of l-cyano-Z-chloroprop-Z- eue. It can however be employed without diiiiculty for the reaction according to the invention.

In order to prepare pure l-cyauopropadi-l,Z-ene, this crude product is distilled by fractionation. 96 pints by weight of a liquid which has a boiling point of 60- 67 C.'/ 95 mm. are obtained'as the main traction. Yield: 74% of the theoretical, based on the l-chloroprop-Z-yne which is introduced. The pure 1-cyanopropadi-l,2-eue has a refractive index of n 1.4612.

Example 2 47 parts by weight of phenyl hydrazine-3-sulphonic acid are dissolved in 300 parts by volume of water by adding 14 parts by weight of sodium carbonate. 17 parts by weight of l-cyanopropadi-LZ-ene are added dropwise to this solution at 35 C. On completing the dropwise addition, the temperature is kept for another 2 "hours at 35 C. 25 parts by volume of concentrated hydrochloric acid are then added, the reaction mixture heated to 98 C. and 80 parts by volume of sodium chloride then added at this temperature. The precipitated crystals are filtered with suction'at 20 C. and washed with a small quantity of 30% sodium chloride solution. Yield: 58 parts by weight of 1-(3'-sulphophenyl)-3- methyl-S-aminopyrazole.

Example 3 42 parts by weight of fi-cyanoethyl hydrazine are dissolved in 100 parts by volume of water and 20 parts by volume of methanol. While maintaining a temperature of approximately 40 C., 33 parts by weight of l-cyanopropadi-LZ-ene are added dropwise to this solution over a period of minutes. After standing for 2 hours at 40 C., a thick oil has formed under a clear orangecoloured solution, the said oil solidifying in the cold. Yield: 66 parts by weight of l-(fi-cyanoethyl)-3-methyl- 5-aminopyrazole (88% of the theoretical). On being crystallised from 530 parts by weight of benzene, the product separates out in the form of colourless crystals With a melting point of 106108 C.

Example 4 47.2 parts by weight of 4-carboxyphenyl hydrazine hydrochloride are dissolved in 250 parts by volume of water and 30 parts by volume of 40% caustic soda solu- :tion. 17 parts by weight of l-cyanopropadi-lJ-ene are *addeddropwise to this solution at 40 C. The-reaction solution is then held for another 2 hours at'80" C. 30 parts by volume of concentrated hydrochloric acid are then added and the mixture heated'to boiling point and then allowed to cool. The precipitated crystals are separated and dissolved in 5% sodium hydroxide solution. With acetic acid, 1-(4-carboxy-phenyl) 3-methyl-5- aminopyrazole is precipitated. M. Pt.: 210-212 C. Yield: 43 parts by weight (80% of the theoretical).

Example 5 28 parts by weight of l-cyanopropadi-l,2-ene are added dropwise to a solution of 30 parts by weight of fi-hydroxyethyl hydrazine in 150 parts by volume of methanol, the reaction mixture being heated almost to boiling point. After boiling for 5 hours, 33 parts by'volume of 'concentrated hydrochloric acid are added and the mixture is boiled for another 30 minutes. The pH value is then adjusted to 7 with sodium hydroxide solution, thereac- 4. tion mixture is concentrated by evaporation on a water bath and the evaporation residue is extracted with 300 parts by volume of alcohol. 40 parts by weight of l-(fihydroxyethyl)-3-methyl-5-aminopyrazole with a boiling point of 190 C./16 mm. and a melting point of 65 C. are obtained from the alcoholic solution by distillation. The yield is 71% of the theoretical.

Example 6 59 parts by weight of 8-sulphonnphthyl-(l)-hydrazine are dissolved at 35 C. in 300 parts by volume of water with the addition of 13.5 parts by weight of sodium carbonate. 17 parts by weight of l-cyanopropadi-LZ-ene are added dropwise to this solution, which now shows a pH value of 7.5, while the temperature is kept by gentle cooling with iced water at 45 C. Thereafter, the reaction mixture is held for 4 hours at 8 C. and 30 parts by volume of concentrated hydrochloric acid are then added and the temperature kept for another hour at this level. On cooling to 20 C. of the calculated quan Example 7 29 parts by weight of 4,4'-dihydrazinostilbene-2,2'-disulphonic acid are dissolved at 35 C. in 300 parts by volume of water containing 8 parts by weight of sodium carbonate. 10 parts by weight of 1-cyanopropadi-1,2-cne are added and the reaction mixture is then heated for 2 hours at 80 C. 20 parts by volume of concentrated hydrochloric acid are then added dropwise and the precipitated slight yellowish green 4,4-bis(5"-amino-3"-methyl pyrazolyl-(1")-stilbene-2,2'-disulphonic acid is recrystallized from dilute sodium chloride solution. The yield is 40%.

l 4 Example 8 21 parts by weight of 1-cyanohexatri-1,2,5-ene are added to a solution of 21.6 parts by weight of phenyl hydrazine in parts by volume of methanol, the temperature rising from 20 to 80 C. After boiling for 10 hours, the methanol is distilled OE and the remaining oil is distilled in vacuo. 1-phenyl-3-(but-3-ene-1-yl)-5- aminopyrazole is obtained, B.P.: 210214 C./13 mm. The yield is 41 parts by weight (96% of the theoretical).

The same product is obtained if 21.6 parts by weight of phenyl hydrazine are reacted in the same way with 21.0 parts by weight of a mixture containing cyanohexa- -tri-1,2,5-ene, cyanohex-S-ene-Z-yne, and less than 10% of cyanohexatri-1,3,5-ene such as is obtained directly as -a crude product, from hex-S-en-Z-ynyl chloride.

The crude 1-cyanohexatri-l,2,5-ene used as starting material is prepared in the following manner:

Using the process indicated in Example 1 for the production of 1-cyanopropadi-1,2-ene, parts by weight 'of hex-S-en-Z-ynyl chloride are reacted with sodium cyanide (as a 30% solution) in 2500 parts by volume of saturated common salt solution which contains 30 parts by weight of cuprous chloride and 30 parts by volume of concentrated hydrochloric acid, at pH 33.4 and at temperature of 80 C. The reaction product is distilled with steam and worked up as described in Example 1. 905 parts by weight (66% of the theoretical) of a liquid which boils at 78-85 C./ 13 mm. and has a refractive index of n 1.4669 .are obtained. This crude product consists of a mixture of 1-cyanohexatri-1,2,5-ene and 1- cyanohex-i-en-Z-yne. As impurity it contains l-cyano- 'hexatri-1,3,5-ene ina quantity of less than 10%.

I This crude product can be used directly for the preparation of l -phenyl-3-(but-3een-l-yl)-5-aminopyrazole.

Pure'cyanohexatri-1,2,5-ene is obtained from the crude product by isomerisation of the 1-cyanohex-5-en-2-yne fraction, by known methods, by treatment with a weakly alkaline agent, such for example as sodium phenate. The pure 1 cyanohexatri-1,2,5-ene has a boiling point of 77- 78 C./ 15 mm. and a refractive index of 11 1.4892.

V the remaining pyrazole .Example 9 16 parts by weight of I-Q-e'ne'a're added to 700 parts by weightof a menthanolic solution containing 46.7 parts by weight of 3-sulphonamidophenyl hydrazine'atTa temperature of 20C., the temperature rising over a period of 30.minute's to'35 C. The mixture is heated for another 2 hours at 50 C., 150 parts by volume of 10% hydrochloric acid are then'added and the solution boiled for 10 minutes. After cooling to'20 C. 1-(3-sulpho'namidophenyl)-3-methyl-5-aminopyrazole is precipitated by adding sodium acetate. The compound melts at 107 C. when recrystallized from water.

Example 10 -the methanol is distilled off until the temperature of the boiling solution is 95 C. By adding sodium acetate, 103 parts by weight of 1-(4-sulphonamidopheny1)-3-methyl- S-aminopyrazole are precipitated, this being 82% of the theoretical; melting point 227-228 C.

Example 11 143 parts by weight of m-chlorophenyl hydrazine hydrochloride are stirred into 500 parts by volume of methanol and the suspension 'is adjusted to pH 8 with 10% sodium hydroxide solution. The solution obtained is now filtered and to the filtrate is added dropwise 54 parts by weight of 1-cyanopropadi-1,2-ene while the temperature is kept at 3050 C. by cooling at intervals.

After 3 hours, a thick crystal magma has formed. By

adding 70 parts by volume of concentrated hydrochloric acid, the pH value is now adjusted to 3 and the methanol is then distilled 01f on a water bath. With sodium hydroxide solution, 160 parts by weight of l-(3-chlorophenyl)-3-methyl-5-aminopyrazole are precipitated from the aqueous distillation residue. Crystallized from alcohol or benzene the compound melts at 138-1 40 C.

Example 12 33 parts by weight of l-cyanopropadi-1,2-ene are added dropwise to 112 parts by weight of 90% hydrazine hydrate, while the temperature is kept at 30-40 C After standing for 16 hours, the water and excess hydrazine hydrate is evaporated in a vacuum of 16 mm. Hg and derivative is also distilled. Boil ing point at 0.05-0.1 mm. Hg 135-139" C. Yield: 33 parts by weight of 3-methyl-5-aminopyrazole, this being i 68% of the theoretical.

Example 13 13.5 parts by weight of 92.5% hydrazine hydrate solution are introduced dropwise into a solution of 33 parts by weight of1-cyanopropadi-1,2-ene in 100 parts by volume of methanol, while the'reaction mixture is kept at atemperature of 20-25 C. by cooling. After the temperature has been held for another two hours at 20 C., 80 parts by volume of water are added and the methanol is distilled ofi until the temperature of the boiling solution is 95 C. After cooling to 10 C., 1-(1- cyanoprop-1en-2-yl)-3-methyle5-aminopyrazole crystal lizes out. Needles with a melting point of 85-86 C. are obtained on recrystallizing from water.

Example 14 temperature and the suspension formed after cooling to comprises reacting at a temperature within the mngeor vstilbene-Z,2'-disulfonic acid'and recovering the 4,4'bi

we. is mixed, enlisting;-wineshans'bfiyaa of 1-cyanopropadi-1,2-ene, the. temperature of theji'reac tion mixture being kept at 70 C. by cooling The clear solution is now held at, 70-80 C. for another 4 hours.- The solution is .thenj adjusted to give an acid reacti o nto Congo by adding 100 parts by volume of'fuminghydrochloric'acid, and-the temperature is maintained for an; v other hour at 70 C. After cooling'to' 20-251. C., "l-j (benzthiazolyl-Z)-3-methyl-5 aminopyrazole, is precipi-i tated by adding, sodium hydroxide solution and 3200 partsby-volume of wateri When crystallizedfrom benzene, it melts at 188-19,0,C'. I r

t 1 r Example15 94.2 parts by weight of a mixture of 20mol percentof 1-cyano-2-chloroprop 2-ene and mol percent offlcyan0propadi-1,2-ene are introduced dropwise into a solu tion of 108 parts by weight of phenyl hydrazine in 200 parts by volume of methanol at 30 C. and the solution obtained is then boiled for 3 hours under reflux. During this time a solution of 12 parts by weight of sodium carbonate in 80 parts by volume of water is added dropwise in order to keep the pH value of the solution at 6-7. After this time, the solution is adjusted to give an acid reaction to Congo by adding 200 parts by volume of 18% hydrochloric acid. The methanol is then distilled OE and 1-phenyl-3-methyl 5-aminopyrazole is precipitated from the residual aqueous solution after cooling to 20-25 C. by the addition of sodium hydroxide solution. It melts.- at 114-115 C.

What we claim is: I 1. Process for the production of substituted S-aminopyrazoles which comprises reacting at a' temperature" within, the range of from about 0 to about C. one mol of a'compound which is a member selected from g the group consisting of 1-cyano-propadi-1,2-ene, 3-alkyl U 1-cyano-propadi-1 ,2-ene, 3-alkanol-l-cyauo-propadilfif 1" ene, l-cyano-hexatri-1,2,5-ene, l-cyano-heptatri-1,2,5-ene, and 2-cyano-butadi-2,3ene with about 0.5 to about 1 mol of a compound having the following general formula:

V R ---NH---NH V in which R is a member selected from the group consist- 11" ing of hydrogen, lower alkyl, lower cyanoalkyl, lower hydroxyalkyl, phenyl, hydroxyphenyl, cyanophenyl, care boxyphenyl, sulfonaphthyl, sulfophenyl, nitrophenyl,

halogenophenyl, .cyanohalogeno-alkyl, naphthyl, 2-benz thiazolyl and 4-hydrazino-2,2-disulfostilbyl radicals, an recovering the substituted 5-aminopyrazole thus formed. I 2. Process according to claim 1 in which said first 1 mentioned group member is l-cyano-p-ropad-i-1,2-ene and saidcompound is employed in admixture with a smaller amount of l-cyano-2-chloro-prop-2-ene. j p 3. Process according to claim '1, in which said first is 1-cyanopropadi-1,2-ene and '5 i said compound. is employed in admixture with [a smaller amount of the corresponding isomeric '1-cyanoprop-2-yne I compound.

4. Process for the productionof-1-phenyl-3rmethyl-5- aminopyrazole which comprises reacting at a temperature withinthe range of from about 30 to about 100 C. about equimolecular amounts of I-cyano-propadi-LZ-ene with phenyl hydrazine and recovering the 1-phenyl-3- methyl-S-aminopyrazole formed. I I j 5. Process for the production of 4,4"-bis-'(5"-am'ino-3"-; methylpyrazolyl-(1") )-stilbene-2,2'-disulfonic acid :which.

from about 35 toabout 80 C. about onemol of lcyanopropadi-1,2-ene with about 0.5 mol 4,4'-hydraz'inm (5" amino 3" methylpyrazolyl (1") estilben 2,2-disulfonic acid formed. 7 if 6. Process forthe production of 1-phenyl-3-.,(but-3.-en 1-yl-5-aminopyrazole which comprisesreacting at a perature within the range of from about .20tozab0flt C.-- about equimolecular amounts of l-cyanoehe A ene with phenylhydrazine and recovering the 1-phenyl-3- (but-3-ene-l-yl-S-aminopyrazole formed.

7. Process for the production of ,1-(4-sulfoamidophenyl)-3-methyl-5-aminopyrazole which comprises reacting at a temperature within the range of from about 30 to about 40 C. about equimolecular amounts of l-cyanopropadi-1,2-ene with 4-sulfoamidophenyl hydrazine, and recovering the 1-(4-su1foamidophenyl)-3-methyl-5-aminopyrazole formed.

8. Process for the production of 3-methyI-5-aminopyrazole which comprises reacting at a temperature within the range of from about 30 to about 40 C. about equimolecular amounts of 1-cyanopropadi-1,2-ene with hydrazine hydrate (90%) and recovering the B-methyl- S-aminopyrazole formed.

9. Process for the production of 1-(benzthiazo1y1-2)- 3-methyl-5-aminopyrazole which comprises reacting at a a temperature within the range of from about 70 to about 80 C. about equimolecular amounts of l-cyanopropadi- 1,2-ene with Z-hydrazine benzthiazol and recovering the '1- benzthiazolyl-2 -3-rnethyl-5-aminopyrazo1e formed.

10. Process for the production of 1-phenyl-3-rnethyl-S- aminopyrazole which comprises reacting at a temperature within the range of from about to about C. about equimolecular amounts of a mixture consisting of 1- cyanopropadi-1,2-ene mol-percent) and l-cyano-Z- chloroprop-Z-ene (20 mol-percent) with phenyl hydrazine and recovering the 1-phenyl-3-methy1-5-aminopyrazole formed.

References Cited in the file of this patent UNITED STATES PATENTS 2,726,248 Kendall et a1. Dec, 6, 1955 UNITED STATES PATENT OFFICE CERTIFICATION OF CORRECTION Patent No; 2 975, 188 March 14, 1961 Heinrich Gold et al.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column l, line 31 for "l-cyrano-hexatrifi? read l-cyanohexatri line 46, for :"lcyano-heptatri-d,2,5-ene"- read lcyano-heptatri-l,2, 5 ene column 2, line 50, after "801d" insert solution, a clear solution being formed. Sodium hydroxide column 4, line 32 for :"slig'ht" read slightly column 5, line 2, for "12-ene" read l-cyanopropadi- 1,2-ene Signed and sealed this, 8th day of August 1961.

(SEAL) Attest:

ERNEST W. SWIDER DAVID L. LADD Attesting Officer Commissioner of Patents 

1. PROCESS FOR THE PRODUCTION OF SUBSTITUTED 5-AMINOPYRAZOLES WHICH COMPRISES REACTING AT A TEMPERATURE WITHIN THE RANGE OF FROM ABOUT 0 TO ABOUT 100*C. ONE MOL OF A COMPOUND WHICH IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF 1-CYANO-PROPADI-1,2-ENE, 3-ALKYL1-CYANO-PROPADI-1,2-ENE, 3-ALKANOL-1-CYANO-PROPADI-1,2ENE, 1-CYANO-HEXATRI,1,2,5-ENE, 1-CYANO-HEPTATRI,1,2,5-ENE, AND 2-CYANO-BUTADI-2,3-ENE WITH ABOUT 0.5 TO ABOUT 1 MOL OF A COMPOUND HAVING THE FOLLOWING GENERAL FORMULA: 